The BMP antagonist gremlin 1 contributes to the development of cortical excitatory neurons, motor balance and fear responses.

Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here, we show that expression of the BMP antagonist Grem1 marks committed layer V and VI glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT; Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA-seq analysis of differentially expressed transcripts between FACS-sorted Grem1-positive and -negative cells was performed. We also generated Emx1-cre-mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers V and VI, and impaired motor balance and fear sensitivity compared with littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex.

Prevalence, associated risk factors; and patient and economic impact of multiple sensory impairment in a multi-ethnic elderly population in Singapore: the PIONEER study.

BACKGROUND: To determine the prevalence, risk factors; and impact on patient health and economic outcomes across the laterality spectrum of multiple sensory impairment (MSI) in a multi-ethnic older Asian population. METHODS: In this population-based study of Singaporeans aged ≥ 60 years, MSI was defined as concomitant vision (visual acuity > 0.3 logMAR), hearing (pure-tone air conduction average > 25 dB), and olfactory (score < 12 on the Sniffin' Sticks test) impairments across the spectrum of laterality (any, unilateral, combination [of unilateral and bilateral], and bilateral). RESULTS: Among 2,057 participants (mean ± SD 72.2 ± 0.2 years; 53.1% female), the national census-adjusted prevalence rates of any, unilateral, combination, and bilateral MSI were 20.6%, 1.2%, 12.2%, and 7.2%, respectively. Older age, male gender, low socioeconomic status (SES), and smoking (all p < 0.05) were independently associated with higher likelihood of any MSI. Compared to those with no sensory loss, those with MSI had significantly decreased mobility (range 5.4%-9.2%), had poor functioning (OR range 3.25-3.45) and increased healthcare costs (range 4-6 folds) across the laterality spectrum. Additionally, bilateral MSI had a significant decrease in HRQoL (5.5%, p = 0.012). CONCLUSIONS: MSI is a highly prevalent medical condition, with 1 in 5; and almost 1 in 10 community-dwelling older Asians having any and bilateral MSI, respectively, with a higher likelihood in men, smokers, and those with low SES. Critically, MSI has a substantial negative impact on patient health and economic outcomes across the laterality spectrum. Sensory testing is critical to detect and refer individuals with MSI for management to improve their functional independence and QoL.

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis.

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. METHODS: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. RESULTS: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor ß was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB-IL34/CCL8 signaling that promotes macrophage chemotaxis. CONCLUSIONS: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.

Adrenaline blocks key cell cycle genes and exhibits antifibrotic and vasoconstrictor effects in glaucoma surgery.

Adrenaline is a sympathomimetic drug used to maintain pupil dilation and to decrease the risk of bleeding. The aim of this study was to demonstrate if adrenaline could exert antifibrotic effects in glaucoma surgery. Adrenaline was tested in fibroblast-populated collagen contraction assays and there was a dose-response decrease in fibroblast contractility: matrices decreased to 47.4% (P = 0.0002) and 86.6% (P = 0.0036) with adrenaline 0.0005% and 0.01%, respectively. There was no significant decrease in cell viability even at high concentrations. Human Tenon's fibroblasts were also treated with adrenaline (0%, 0.0005%, 0.01%) for 24 h and RNA-Sequencing was performed on the Illumina NextSeq 2000. We carried out detailed gene ontology, pathway, disease and drug enrichment analyses. Adrenaline 0.01% upregulated 26 G1/S and 11 S-phase genes, and downregulated 23 G2 and 17 M-phase genes (P < 0.05). Adrenaline demonstrated similar pathway enrichment to mitosis and spindle checkpoint regulation. Adrenaline 0.05% was also injected subconjunctivally during trabeculectomy, PreserFlo Microshunt and Baerveldt 350 tube surgeries, and patients did not experience any adverse effects. Adrenaline is a safe and cheap antifibrotic drug that significantly blocks key cell cycle genes when used at high concentrations. Unless contraindicated, we recommend subconjunctival injections of adrenaline (0.05%) in all glaucoma bleb-forming surgeries.

3,4-Diaminopyrazolo[3,4-d]pyrimidines: a new three-component microwave-assisted synthesis and anti-leukemic properties.

A convenient method for the synthesis of N3,N4-disubstituted 3,4-diaminopyrazolo[3,4-d]pyrimidines was developed using a three-component reaction of 3,5-diaminopyrazole-4-carbonitriles with primary amines and orthoesters. The preparation of 116 examples demonstrated the good scope of the reaction, which tolerated variations in the substrate structure and was particularly efficient under microwave irradiation. The short reaction time and chromatography-free product isolation add practicality to this method. The anti-leukemic activity was assessed in vitro using K562 and Jurkat T cells, and the selectivity of the most active compounds was evaluated using non-cancerous MRC5 cells. The most promising compound inhibited Jurkat T cells with a GI50 value of 0.5 µM and a selectivity index of 65.

Pre-operative erector spinae plane block should be considered a viable option for laparoscopic colectomies.

BACKGROUND: The Erector Spinae Plane (ESP) block is a recent development in the field of regional anaesthesia and has been increasingly explored for abdominal surgeries to reduce opioid use and improve pain control. Colorectal cancer is the commonest cancer in multi-ethnic Singapore and requires surgery for curative treatment. ESP is a promising alternative in colorectal surgeries, but few studies have evaluated its efficacy in such surgeries. Therefore, this study aims to evaluate the use of ESP blocks in laparoscopic colorectal surgeries to establish its safety and efficacy in this field. METHODS: A prospective two-armed interventional cohort study comparing T8-T10 ESP blocks with conventional multimodal intravenous analgesia for laparoscopic colectomies was conducted in a single institution in Singapore. The decision for doing an ESP block versus conventional multimodal intravenous analgesia was made by a consensus between the attending surgeon and anesthesiologist. Outcomes measured were total intra-operative opioid consumption, post-operative pain control and patient outcome. Post-operative pain control was measured by pain score, analgesia use, and amount of opioids consumed. Patient outcome was determined by presence of ileus. RESULTS: A total of 146 patients were included, of which 30 patients received an ESP block. Overall, the ESP group had a significantly lower median opioid usage both intra-operatively and post-operatively (p = 0.031). Fewer patients required patient-controlled analgesia and rescue analgesia post-operatively for pain control (p < 0.001) amongst the ESP group. Pain scores were similar and post-operative ileus was absent in both groups. Multivariate analysis found that the ESP block had an independent effect on reducing intra-opioid consumption (p = 0.014). Multivariate analysis of post-operative opioid use and pain scores did not yield statistically significant results. CONCLUSIONS: The ESP block was an effective alternative regional anaesthesia for colorectal surgery that reduced intra-operative and post-operative opioid use while attaining satisfactory pain control.

The Role and Effect of Multimodal Prehabilitation Before Major Abdominal Surgery: A Systemic Review and Meta-Analysis.

BACKGROUND: For patients undergoing abdominal surgery, multimodal prehabilitation, including nutrition and exercise interventions, aims to optimize their preoperative physical and physiological capacity. This meta-analysis aims to explore the impact of multimodal prehabilitation on surgical and functional outcomes of abdominal surgery. METHODS: Medline, Embase and CENTRAL were searched for articles about multimodal prehabilitation in major abdominal surgery. Primary outcomes were postoperative complications with a Clavien-Dindo score ≥3, and functional outcomes, measured by the 6-Minute Walking Test (6MWT). Secondary outcome measures included the quality-of-life measures. Pooled risk ratio (RR) and 95% confidence interval (CI) were estimated, with DerSimonian and Laird random effects used to account for heterogeneity. RESULTS: Twenty-five studies were included, analysing 4,210 patients across 13 trials and 12 observational studies. Patients undergoing prehabilitation had significantly fewer overall complications (RR = 0.879, 95% CI 0.781-0.989, p = 0.034). There were no significant differences in the rates of wound infection, anastomotic leak and duration of hospitalization. The 6MWT improved preoperatively in patients undergoing prehabilitation (SMD = 33.174, 95% CI 12.674-53.673, p = 0.005), but there were no significant differences in the 6MWT at 4 weeks (SMD = 30.342, 95% CI - 2.707-63.391, p = 0.066) and 8 weeks (SMD = 24.563, 95% CI - 6.77-55.900, p = 0.104) postoperatively. CONCLUSIONS: As preoperative patient optimization shifts towards an interdisciplinary approach, evidence from this meta-analysis shows that multimodal prehabilitation improves the preoperative functional capacity and reduces postoperative complication rates, suggesting its potential in effectively optimizing the abdominal surgery patient. However, there is a large degree of heterogenicity between the prehabilitation interventions between included articles; hence results should be interpreted with caution.

Ocular toxicity following carboplatin chemotherapy for neuroendocrine tumour of the bladder.

INTRODUCTION: Carboplatin is a commonly used platinum analogue chemotherapeutic agent that is similar to cisplatin but is known to be better tolerated. This case report outlines a case of ocular toxicity following carboplatin chemotherapy used for the management of a neuroendocrine tumour of the bladder. CASE REPORT: A 70-year-old man with a history of neuroendocrine bladder cancer underwent chemotherapy with carboplatin and etoposide. He presented 4 weeks following his fourth chemotherapy cycle with a 1-week history of right eye blurriness. The patient had suffered a similar episode 2 weeks following his third chemotherapy cycle in his left eye. Carboplatin-induced ocular toxicity was suspected and his vision remained stable following cessation of carboplatin chemotherapy. DISCUSSION: Current literature on carboplatin-induced ocular toxicity remains scanty, however, previous cases have reported symptoms beginning 5 days to 2 weeks following carboplatin use. Visual disturbance in the form of altered colour vision, blind spot, blurred vision and metamorphopsia have been reported by previous literature. This case report emphasised a case of bilateral sequential blurring of vision following carboplatin chemotherapy. CONCLUSION: It remains critical for ophthalmologists and oncologists to look out for ocular side effects of chemotherapy due to its devastating effects.

The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. METHODS: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. RESULTS: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor ß and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5+ intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)-mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis. CONCLUSIONS: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

Outcomes of kidney transplantation in patients with myeloma and amyloidosis in the USA.

BACKGROUND: Recent improvement in treatment and patient survival has opened the eligibility of kidney transplantation to patients who developed end-stage kidney disease (ESKD) from plasma cell dyscrasias (PCDs). Data on clinical outcomes in this population are lacking. METHODS: We conducted a retrospective study of United Network for Organ Sharing/Organ Procurement and Transplantation Network dataset (2006-2018) to compare patient and graft outcomes of kidney transplant recipients with ESKD due to PCD versus other causes. RESULTS: Among 168 369 adult first kidney transplant recipients, 0.22-0.43% per year had PCD as the cause of ESKD. The PCD group had worse survival than the non-PCD group for both living and deceased donor types {adjusted hazard ratio [aHR] 2.24 [95% confidence interval (CI) 1.67-2.99] and aHR 1.40 [95% CI 1.08-1.83], respectively}. The PCD group had worse survival than the diabetes group, but only among living donors [aHR 1.87 (95% CI 1.37-2.53) versus aHR 1.16 (95% CI 0.89-1.2)]. Graft survival in patients with PCD were worse than non-PCD in both living and deceased donors [aHR 1.72 (95% CI 1.91-2.56) and aHR 1.30 (95% CI 1.03-1.66)]. Patient and graft survival were worse in amyloidosis but not statistically different in multiple myeloma compared with the non-PCD group. CONCLUSION: The study data are crucial when determining kidney transplant eligibility and when discussing transplant risks in patients with PCD.

A systematic review and meta-analysis of dabigatran peak and trough concentration in adults.

Dabigatran etexilate is an oral direct thrombin inhibitor used in preventing thromboembolism in patients with atrial fibrillation and several other conditions. Routine dabigatran concentration monitoring is not recommended in clinical practice; however, measurement of dabigatran concentration may be required in several conditions. This study aims to pool the peak and trough dabigatran concentration from real-world studies. A systematic review was performed to identify studies that measured the peak and trough dabigatran concentrations. Observational studies reporting dabigatran peak or trough concentrations and patients' clinical characteristics of either sex, age or weight were included. Random-effect meta-analyses and metaregression were conducted to pool dabigatran concentrations and to identify the correlation between factors affecting dabigatran concentrations. Fifteen studies with a total of 1226 patients were included. The pooled peak dabigatran concentration was 133 ng/mL (95% CI: 113-154, I2  = 86%, n = 655), while the pooled dabigatran trough concentration was 80 ng/mL (95% CI: 69-91, I2  = 93%, n = 1010). Metaregression analyses suggested that age is significantly correlated to trough concentration, while body weight and creatinine clearance significantly correlated to peak concentration. Subgroup results revealed that dabigatran concentration when measured with liquid chromatography-tandem mass spectrometry was higher than haemoclot thrombin inhibitor assay. Several guidelines have proposed dabigatran concentrations target range and the pooled dabigatran concentrations were in line with the suggested range. Further studies to correlate dabigatran concentrations and clinical outcomes is warranted to improve the safety and efficacy monitoring of dabigatran therapy.

Systematic review and meta-analysis of postoperative pain and symptoms control following laser haemorrhoidoplasty versus Milligan-Morgan haemorrhoidectomy for symptomatic haemorrhoids: a new standard.

PURPOSE: Haemorrhoidal disease (HD) plagues one in every ten people, with a plethora of surgical treatment modalities, of which laser haemorrhoidoplasty (LHP) is a relatively novel option. This systematic review and meta-analysis objectively evaluated the efficacy, safety, and tolerability of LHP compared against conventional (Milligan-Morgan) open haemorrhoidectomy (CoH). METHOD: A comprehensive search of MEDLINE, EMBASE, CENTRAL, and Google Scholar was conducted. Randomised controlled trials (RCTs) and comparative cohort studies (CCSs) which compared LHP against CoH were included, with postoperative pain as the primary outcome. Secondary outcomes included intraoperative characteristics, short- and moderate-term outcome, and complications. RESULTS: A total of 12 studies (6 RCTs and 6 CCSs), with a total of 1824 patients, were analysed. LHP resulted in reduced postoperative pain for the first day (mean difference of 2.07 visual analogue scale units), week, and month. The mean dosage and duration of postoperative analgesia use was similarly lower, with a mean difference of 4.88 mg (morphine) and 2.25 days, respectively. Crucially, recurrence was equivocal (HR: 0.72, CI: 0.21-2.40) at a mean follow-up duration of 8.58 ± 9.55 months. LHP resulted in lower blood loss and was 12.74 min shorter on average. LHP's postoperative recovery time was 9.03 days less with equivalent or decreased risk of most short- and moderate-term complications except anal thrombosis. CONCLUSION: Our study suggests that LHP is more tolerable than CoH, providing patients with superior postoperative quality of life at equivalent moderate-term efficacy. These findings contribute to improved understanding of LHP and its potential at enhancing the quality of HD care.

Did the COVID-19 lockdown result in a delay of colorectal cancer presentation and outcomes? A single centre review.

PURPOSE: The COVID-19 pandemic and resultant lockdown measures potentially delay management of non-communicable, life-limiting diseases like colorectal cancer (CRC) through avoidance of healthcare facilities by the public and diversion of resources within healthcare systems. This study aims to evaluate the impact of Singapore's "Circuit Breaker (CB)" lockdown measures on CRC disease presentation and short-term surgical outcomes, while comparing Singapore's approach against other countries which employed similar lockdown measures. METHODS: Patients whose initial diagnosis of CRC was made within the 6-month pre-CB (6/10/19-6/4/20) ("pre-CB group") and post-CB (7/4/20-7/10/20) ("post-CB group") period were enrolled retrospectively. The groups were compared based on severity of disease on presentation and short-term operative outcomes. RESULTS: In total, 105 patients diagnosed with CRC were enrolled in this study. When comparing pre-CB and post-CB groups, there was no significant difference in stage of CRC on presentation (p = 0.850). There was also no increase in need for emergent operations (p = 0.367). For patients who had undergone an operation, postoperative morbidity was not significantly higher in the post-CB group (p = 0.201). Both groups of patients had similar length of stay in the hospital (p = 0.438). CONCLUSION: Unlike similar high-income countries, Singapore did not see later stage disease on presentation and poorer operative outcomes after lockdown measures. Possible reasons include lesser healthcare avoidance behaviours amongst Singaporeans, and adequate preparation of resources and contingency plans formed by hospitals after previous pandemics.

Post-operative healing and long-term stability after mastoid cavity reconstruction using the middle temporal artery and inferior musculoperiosteal flaps.

PURPOSE: This study aims to evaluate the surgical outcomes with the use of a combination of the middle temporal artery (MTA) flap and the inferior musculoperiosteal (IMP) flap for mastoid obliteration after canal wall down mastoidectomy. METHODS: Seventy-five patients who have undergone canal wall down mastoidectomy and mastoid obliteration with the MTA and the IMP flaps at a single tertiary hospital were included. Surgical outcomes measured included the creation of a dry mastoid cavity as measured by a previously developed semi-quantitative scale, mastoid cavity epithelization time, rate of revision surgery needed, and rate of recurrent cholesteatoma. RESULTS: Patients were followed up for a median of 29 months. The median time to epithelization of the mastoid cavity was 2 months. At 1 and 3 months, 36.0% and 76.0% of patients had grade 0 and grade 1 cavities, respectively, with either a dry cavity or one or less episodes of mild otorrhea or sensation of wetness. Hundred percent of the patients achieved a grade 2 (more than one episode of otorrhea or the presence of granulation tissue that promptly resolved with simple treatment) or better cavity at 3 months. One patient re-presented with a grade 3 cavity with uncontrolled infection and daily otorrhea secondary to an attic perforation that manifested at 6 months, requiring revision surgery. There were no recurrent cholesteatomas during the follow-up period. CONCLUSIONS: The use of the MTA and the IMP flaps for mastoid obliteration may be considered as an adjunct to achieving a safe, dry ear after canal wall down mastoidectomy.

Stromal DLK1 promotes proliferation and inhibits differentiation of the intestinal epithelium during development.

The stem/progenitor cells of the developing intestine are biologically distinct from their adult counterparts. Here, we examine the microenvironmental cues that regulate the embryonic stem/progenitor population, focusing on the role of Notch pathway factor delta-like protein-1 (DLK1). mRNA-seq analyses of intestinal mesenchymal cells (IMCs) collected from embryonic day 14.5 (E14.5) or adult IMCs and a novel coculture system with E14.5 intestinal epithelial organoids were used. Following addition of recombinant DLK1 (rDLK) or Dlk1 siRNA (siDlk1), epithelial characteristics were compared using imaging, replating efficiency assays, qPCR, and immunocytochemistry. The intestinal phenotypes of littermate Dlk1+/+ and Dlk1-/- mice were compared using immunohistochemistry. Using transcriptomic analyses, we identified morphogens derived from the embryonic mesenchyme that potentially regulate the developing epithelial cells, to focus on Notch family candidate DLK1. Immunohistochemistry indicated that DLK1 was expressed exclusively in the intestinal stroma at E14.5 at the top of emerging villi, decreased after birth, and shifted to the intestinal epithelium in adulthood. In coculture experiments, addition of rDLK1 to adult IMCs inhibited organoid differentiation, whereas Dlk1 knockdown in embryonic IMCs increased epithelial differentiation to secretory lineage cells. Dlk1-/- mice had restricted Ki67+ cells in the villi base and increased secretory lineage cells compared with Dlk1+/+ embryos. Mesenchyme-derived DLK1 plays an important role in the promotion of epithelial stem/precursor expansion and prevention of differentiation to secretory lineages in the developing intestine.NEW & NOTEWORTHY Using a novel coculture system, transcriptomics, and transgenic mice, we investigated differential molecular signaling between the intestinal epithelium and mesenchyme during development and in the adult. We show that the Notch pathway factor delta-like protein-1 (DLK1) is stromally produced during development and uncover a new role for DLK1 in the regulation of intestinal epithelial stem/precursor expansion and differentiation to secretory lineages.

Outcomes Among Patients Hospitalized With COVID-19 and Acute Kidney Injury.

RATIONALE & OBJECTIVE: Outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19) and acute kidney injury (AKI) are not well understood. The goal of this study was to investigate the survival and kidney outcomes of these patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Patients (aged≥18 years) hospitalized with COVID-19 at 13 hospitals in metropolitan New York between March 1, 2020, and April 27, 2020, followed up until hospital discharge. EXPOSURE: AKI. OUTCOMES: Primary outcome: in-hospital death. SECONDARY OUTCOMES: requiring dialysis at discharge, recovery of kidney function. ANALYTICAL APPROACH: Univariable and multivariable time-to-event analysis and logistic regression. RESULTS: Among 9,657 patients admitted with COVID-19, the AKI incidence rate was 38.4/1,000 patient-days. Incidence rates of in-hospital death among patients without AKI, with AKI not requiring dialysis (AKI stages 1-3), and with AKI receiving dialysis (AKI 3D) were 10.8, 31.1, and 37.5/1,000 patient-days, respectively. Taking those without AKI as the reference group, we observed greater risks for in-hospital death for patients with AKI 1-3 and AKI 3D (HRs of 5.6 [95% CI, 5.0-6.3] and 11.3 [95% CI, 9.6-13.1], respectively). After adjusting for demographics, comorbid conditions, and illness severity, the risk for death remained higher among those with AKI 1-3 (adjusted HR, 3.4 [95% CI, 3.0-3.9]) and AKI 3D (adjusted HR, 6.4 [95% CI, 5.5-7.6]) compared with those without AKI. Among patients with AKI 1-3 who survived, 74.1% achieved kidney recovery by the time of discharge. Among those with AKI 3D who survived, 30.6% remained on dialysis at discharge, and prehospitalization chronic kidney disease was the only independent risk factor associated with needing dialysis at discharge (adjusted OR, 9.3 [95% CI, 2.3-37.8]). LIMITATIONS: Observational retrospective study, limited to the NY metropolitan area during the peak of the COVID-19 pandemic. CONCLUSIONS: AKI in hospitalized patients with COVID-19 was associated with significant risk for death.

Stem cell-directed therapies for osteoarthritis: The promise and the practice.

Osteoarthritis (OA) is a disease of an entire synovial joint characterized by clinical symptoms and distortion of joint tissues, including cartilage, muscles, ligaments, and bone. Although OA is a disease of all joint tissues, it is a defined accessible compartment and is thus amenable to topical surgical and regenerative therapies, including stem cells. All tissues arise from stem progenitor cells, and the relative capacity of different cellular compartments, and different individuals, to renew tissues into adulthood may be important in the onset of many different degenerative diseases. OA is driven by both mechanical and inflammatory factors, but how these factors affect the proliferation and differentiation of cells into cartilage in vivo is largely unknown. Indeed, our very basic understanding of the physiological cellular kinetics and biology of the stem-progenitor cell unit of the articular cartilage, and how this is influenced by mechano-inflammatory injury, is largely unknown. OA seems, rather deceptively, to be the low-hanging fruit for stem cell therapy. Without the basic understanding of the stem cell and progenitor unit that generate and maintain articular cartilage in vivo, we will continue to waste opportunities to both prevent and manage this disease. In this review, we discuss the biology of chondrogenesis, the stem cell populations that support articular cartilage in health and disease, and future opportunities afforded through the translation of basic articular chondrocyte stem cell biology into new clinical therapies.

Potential mechanisms linking psychological stress to bone health.

Chronic psychological stress affects many body systems, including the skeleton, through various mechanisms. This review aims to provide an overview of the factors mediating the relationship between psychological stress and bone health. These factors can be divided into physiological and behavioural changes induced by psychological stress. The physiological factors involve endocrinological changes, such as increased glucocorticoids, prolactin, leptin and parathyroid hormone levels and reduced gonadal hormones. Low-grade inflammation and hyperactivation of the sympathetic nervous system during psychological stress are also physiological changes detrimental to bone health. The behavioural changes during mental stress, such as altered dietary pattern, cigarette smoking, alcoholism and physical inactivity, also threaten the skeletal system. Psychological stress may be partly responsible for epigenetic regulation of skeletal development. It may also mediate the relationship between socioeconomic status and bone health. However, more direct evidence is required to prove these hypotheses. In conclusion, chronic psychological stress should be recognised as a risk factor of osteoporosis and stress-coping methods should be incorporated as part of the comprehensive osteoporosis-preventing strategy.

Bearing fixing: A new computer algorithm method for subjective determination of astigmatism.

PURPOSE: This article aims to illustrate the principles of bearing fixing, a new computer-controlled procedure for subjective determination of astigmatism, and to compare it with conventional clinician-controlled Jackson crossed-cylinder refraction. METHODS: The principles and method for bearing fixing are described. Astigmatism was measured using bearing fixing and Jackson cross-cylinder twice on 20 visually normal participants aged between 18 and 34 years. After final sphere adjustment, acuity measurements were made with each refraction estimate. RESULTS: Bearing fixing results could be obtained for all participants. Mean bearing fixing cylinder magnitude was slightly higher than Jackson cross-cylinder measures of cylinder magnitude, by 0.05D. Using vector analysis to take into account cylinder power and axis, mean bearing fixing astigmatism was not significantly different from cross-cylinder astigmatism, but did have higher test-retest variability (p < 0.05). Acuity with bearing fixing and cross-cylinder corrections did not significantly differ in average value or repeatability. CONCLUSIONS: Bearing fixing is a feasible method for subjective determination of astigmatism, and there are a number of potential improvements to the method which could make it faster and more precise.

Asymmetric Synthesis of Fluorinated Allenes by Rhodium-Catalyzed Enantioselective Alkylation/Defluorination of Propargyl Difluorides with Alkylzincs.

The reaction of propargyl difluorides R1 CF2 C≡CR2 with alkylzincs R3 ZnCl giving axially chiral fluorinated allenes R1 FC=C=CR2 R3 with high enantioselectivity (up to 99 % ee) was found to be catalyzed by a chiral diene/rhodium complex. A key step in the catalytic cycle is selective elimination of one of the enantiotopic fluorides at the ß-position of an alkenyl-Rh intermediate, which is generated by regioselective addition of R3 -Rh onto the triple bond of the starting difluorides.